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基于HMGB1-RAGE信号通路研究奥拉米特预防抗结核药物性肝损伤的作用机制
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| 篇名： | 基于HMGB1-RAGE信号通路研究奥拉米特预防抗结核药物性肝损伤的作用机制 |
| TITLE： | Study on the Prevention Mechanism of Anti-tuberculosis Drug-induced Liver Injury with Orazamide Based on HMGB1-RAGE Signaling Pathway |
| 摘要： | 目的：初步探讨奥拉米特预防抗结核药物性肝损伤（ATB-DILI）的可能机制。方法：将60只昆明小鼠随机分为空白组、模型组、阳性对照组[甘草酸二铵60mg/（kg·d）]和奥拉米特低、中、高剂量组[80、160、320mg/（kg·d）]，每组10只。除空白组外，其余各组小鼠均灌胃异烟肼[75mg/（kg·d）]+利福平[75mg/（kg·d）]14d以复制ATB-DILI模型。与此同时，各给药组小鼠灌胃相应药液，空白组和模型组小鼠灌胃生理盐水，给药体积均为20mL/（kg·d），每天给药1次，连续给药14d。每天观察并记录小鼠生长发育、精神状态、饮食等一般情况。末次给药后，计算其肝指数，以苏木精-伊红（HE）染色法观察小鼠肝组织病理学改变，采用链霉抗生物素蛋白-生物素-过氧化物酶复合物（SABC）免疫组化法检测其肝组织中高速泳动族蛋白B1（HMGB1）、核因子κB（NF-κB）的阳性表达情况，采用酶联免疫吸附法检测其血清中肝功能指标水平和肝组织中晚期糖基化终末产物受体（RAGE）、肿瘤坏死因子α（TNF-α）的表达情况。结果：与空白组比较，模型组小鼠生长发育迟缓，食欲、精神等差，肝指数和血清中总胆红素、直接胆红素、丙氨酸转氨酶、天冬氨酸转氨酶、碱性磷酸酶（ALP）、总胆汁酸（TBA）、γ-谷氨酰转肽酶水平均显著升高（P＜0.05）；肝小叶结构紊乱，肝细胞变性、坏死，并伴炎症细胞浸润；肝组织中HMGB1、NF-κB、RAGE、TNF-α的表达均显著增强（P＜0.05）。与模型组比较，奥拉米特低、中、高剂量组和阳性对照组小鼠的一般情况均有不同程度好转，肝指数和上述血清指标均显著降低（P＜0.05），肝组织病理学变化均有不同程度改善，肝组织中HMGB1、NF-κB、RAGE、TNF-α的表达均显著降低（P＜0.05），且奥拉米特高剂量组上述指标改善效果均显著优于奥拉米特低、中剂量组（P＜0.05），ALP、TBA水平显著低于阳性对照组（P＜0.05）。结论：奥拉米特能够预防异烟肼联合利福平所致的小鼠ATB-DILI，其机制可能与下调肝组织HMGB1和RAGE蛋白表达、抑制炎症因子分泌有关。 |
| ABSTRACT： | OBJECTIVE：To prelimi narily investigate the possible mechanism of orazamide to prevent anti-tuberculosis drug-induced liver injury （ATB-DILI）. METHODS ：A total of 60 Kunming mice were randomly divided into blank group ，model group，positive control group [diammonium glycyrrhizinate 60 mg/（kg·d）]，orazamide low-dose ，medium-dose and high-dose groups [ 80，160，320 mg/（kg·d）]，with 10 mice in each group. Except for blank group ，other groups were given isoniazid [ 75 mg/（kg·d）]+rifampicin [ 75 mg/（kg·d）] for 14 days intragastrically to induce ATB-DILI model. At the same time ，administration groups were given relevant medicine intragastrically ，blank group and model group were given normal saline intragastrically. The administration volume was 20 mL/（kg·d），once a day ，for consecutive 14 days. The general conditions of the mice were observed and recorded every day ，such as growth and development ，mental and diet state. After last medication ，liver index was calculated ， and HE staining was adopted to observe pathological changes of liver tissue of mice. The positive expression of high mobility group protein B 1 （HMGB1） and NF-κ B in liver tissue were detected by streptavidin biotin-peroxidase complex （SABC） immuno- histochemistry. The serum levels of liver function indexes in serum ，the protein expression of advanced glycation end product receptor（RAGE）and TNF-α in liver tissue were detected by ELISA. RESULTS：Compared with blank group ，the growth and development of mice in the model group were slow ，and their appetite and spirit were poor. The liver index ，serum levels of TBIL ， DBIL，ALT，AST，ALP，TBA and γ-GT were increased significantly （P＜0.05）. Structural disorder of liver lobules ，degeneration and necrosis of liver cells and inflammatory cell infiltration were observed. The expression of HMGB 1，NF-κB，RAGE and TNF-α in liver tissue were elevated significantly （P＜0.05）. Compared with model group ，the general condition of mice were all improved to different extents in orazamide low-dose ，medium-dose and high-dose groups ，positive control group ，while liver index and above serum indexes were all decreased significantly （P＜0.05）. The pathological changes of liver tissue were all improved to different extents ，while the protein expression of HMGB 1，NF-κB，RAGE and TNF-α were all decreased significantly（P＜0.05）. The improvement of above indexes in orazamide high-dose group were all significantly better than orazamide low-dose and medium-dose groups （P＜0.05）；the levels of ALP and TBA in orazamide high-dose group were significantly lower than positive control group （P＜0.05）. CONCLUSIONS ：Orazamide can prevent ATB-DILI induced by isoniazid combined with rifampicin in mice，the mechanism of which may be associated with down-regulating the protein expression of HMGB 1 and RAGE in liver tissue and inhibiting the secretion of inflammatory factors. |
| 期刊： | 2021年第32卷第18期 |
| 作者： | 何玲，唐简，彭忠田 |
| AUTHORS： | HE Ling，TANG Jian，PENG Zhongtian |
| 关键字： | 奥拉米特；抗结核药物性肝损伤；高速泳动族蛋白B1-晚期糖基化终末产物受体信号通路；小鼠 |
| KEYWORDS： | Orazamide；Anti-tuberculosis drug-induced liver injury ；HMGB1-RAGE signaling pathway ；Mice |
| 阅读数： | 209 次 |
| 本月下载数： | 5 次 |
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